Nutraceuticals are a multibillion dollar industry in the USA. For reasons of both marketing strategy and antidotal evidence, oriental herbals are touted as having great promise for ameliorating a variety of diseases. Oriental herbal supplements are perhaps the best example of products readily consumed by the American public without adequate knowledge of efficacy or safety. As a case in point, an active ingredient in Chinese herbals prepared from Polygonum tinctorium has been isolated that inhibits cyclin-dependent kinases and glycogen synthase kinase thereby inhibiting proliferation of leukemia cells. Extracts from this plant enhance detoxication processes and they have potent antiinflammatory properties. The biological activity of the active ingredient has been traced to an indole-metabolite of tryptophan that is further metabolized to two end products, indigo and indirubin. Indirubin is now known to be the active anti-neoplastic and anti-inflammatory ingredient in Polygonum tinctorium extracts. Indirubin binds to the cytosolic aryl hydrocarbon receptor (AhR), a transcription factor, with high affinity and activates the translocation of the ligand-receptor complex to the nucleus, leading to the expression of a suite of genes. Surprisingly indirubin binds to the AhR with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like affinity. High affinity binding of indirubin to the AhR is an alarming observation because most agents that bind with high affinity to the AhR are immunotoxic. Our preliminary data show that indirubin is a potent inducer of CYP1A1 in differentiated human macrophages. Furthermore indirubin potentiates LPS-stimulated macrophage activation. In addition, indirubin alters the expression of indoleamine 2, 3-dioxygenase (IDO), an enzyme not yet described as being linked to AhR activation. IDO modulation by indirubin is intriguing because several recent studies confirm that tryptophan metabolism and reduction by IDO-alters T-cell responses. Taken together with other preliminary data, including gene array analysis, RT-PGR and protein expression profiles, it appears that indirubin has the potential to act as a TCDD-like compound. To date information regarding potentially adverse effects of novel plant-derived AhR ligands like indirubin on immune function is lacking of particular importance to immune function, cellular and molecular events involved in macrophage differentiation and activation leading to altered proinflammatory events may be affected by plant-based AhR- ligands. The following proposal tests the hypothesis that indirubin is a potent immunotoxic compound.